This invention relates to an improved process for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and of the trihydrated monosodium salt thereof, respectively known by the International Nonproprietary Names (INN) thereof as alendronic acid and sodium alendronate, and which are useful for the treatment and prevention of diseases involving bone resorption, such as malign hypercalcemia, Paget""s disease, osteoporosis, etc.
U.S. Pat. No. 4,407,761 describes the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, by treating 4-aminobutyric acid (GABA) with a phosphonation reactant, followed by hydrolysis of the reaction mixture by the addition of concentrated hydrochloric acid and subsequent heating of said mixture. The said patent describes the use of three phosphonation mixtures: H3PO3/PCl3, H3PO3/PCl5 and H3PO3/POCl3.
U.S. Pat. No. 4,705,651 is bound to the use of a phosphonation mixture consisting of a mixture of H3PO3/PCl3 and to a certain GABA/H3PO3/PCl3 stoichiometry.
It is hard to adapt these processes to industrial production, since the reaction mixture of the phosphonation step is not homogenous and tends to solidify, preventing stirring, and also the yields obtained are variable. Under these conditions, the subsequent hydrolysis step entails substantial risk, due to the presence of small drops of PCl3 occluded in the reaction mixture and which may cause local overheating on contact with the hydrolyzing agent and also explosion of the gases generated.
U.S. Pat. No. 4,922,007 describes the use of methanesulfonic acid to avoid the lack of homogeneity and the solidification of the reaction mixture during the phosphonation step, to which end the ternary system H3PO3/PCl3/CH3SO3H is proposed. This system has been developed in other later patents as far as complementary aspects are concerned. Among such patents there may be cited EP-A-0 462 663 and U.S. Pat. No. 5,019,651, on the control of pH in the hydrolysis phase, and EP-A-0 715 631 and U.S. Pat. No. 5,648,491, concerning a continuous process.
The present inventors are unaware of other descriptions of direct phosphonation of 4-aminobutyric acid proposing phosphonation reactants other than the above mentioned mixtures.
U.S. Pat. No. 5,039,819 describes an method of indirect phosphonation of 4-aminobutyric acid requiring the protection of the amino group with phthalic anhydride, activation of the acid with thionyl chloride, reaction with an alkyl phosphite and, finally, final hydrolysis of the phosphonic esters obtained, a time-consuming process which is inappropriate for industrial purposes.
There is, therefore, a need to develop alternative processes for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and salts thereof, allowing the industrial preparation of these products to be simplified.
The object of the present invention is a new process for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and of the trihydrated monosodium salt thereof, which is easily adapted to industrial application, with good yields, which does not require the use of reactants such as PCl3, PCl5 or POCl3, which are highly toxic and hazardous products for the environment, and in which the reaction mixture does not solidify.
The present inventors have discovered that a mixture of phosphorous acid and methanesulfonic anhydride allows the direct bisphosphonation of 4-aminobutyric acid to give the corresponding 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid with good results and without the reaction mixture solidifying.
Consequently, the process according to the invention consists of reacting 4-aminobutyric acid with a phosphonation mixture and hydrolyzing the resulting reaction product to subsequently isolate, by an appropriate pH adjustment, the free acid or the monosodium salt. The essential feature of this process is that the phosphonation mixture is formed by phosphorous acid and methanesulfonic anhydride.
Although this phosphonation mixture may also be used jointly with other auxiliary phosphonation reactants, such as PCl3, PCl5 or POCl3, in a specially preferred form the phosphonation mixture is formed exclusively by phosphorous acid and methanesulfonic anhydride.
In the said phosphonation mixture, the phosphorous acid/methanesulfonic anhydride molar ratio may range from 2:5 to 5:2, although a phosphorous acid/methanesulfonic anhydride molar ratio of 1:1 is preferred.
With regard to the 4-aminobutyric acid/phosphorous acid molar ratio, the latter being the reactant providing the two phosphonic groups to the structure of the end products, it may range from 2:1 to 5:1, 3:1 being preferred.
A preferred embodiment of the process according to the invention comprises the following steps:
(i) reacting 4-aminobutyric acid with phosphorous acid in the presence of methanesulfonic anhydride,
(ii) hydrolyzing the reaction mixture with water,
(iii) adjusting the pH of the hydrolyzed mixture to 4.3 with the addition of a solution of sodium hydroxide or of a basic sodium salt,
(iv) precipitating the trihydrated monosodium salt by cooling and recovering the product obtained by filtration and drying, and if it is desired to obtain the free acid,
(v) converting the salt obtained into the corresponding acid by neutralization thereof with an acid stronger than the 4-amino-1-hydroxybutilidene-1,1-bisphosphonic acid.
The most appropriate temperatures for the bisphosphonation reaction range from 45xc2x0 C. to 125xc2x0 C., preferably from 65xc2x0 C. to 75xc2x0 C.
Although it is not necessary, the bisphosphonation reaction is preferably conducted in the presence of inert organic solvents which do not solubilize the reaction product. An inert solvent is understood to be one which, in the opinion of the man or the art, does not react substantially with the reactants involved. Preferred among the inert solvents are the aromatic hydrocarbons such as xylene, toluene, benzene, etc.
Once the bisphosphonation reaction is complete, it is interrupted by the addition of water at a temperature ranging from 0xc2x0 C. to 90xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. The resulting mixture is heated to a temperature above 50xc2x0 C., preferably to the reflux temperature of said mixture, to ensure complete hydrolysis. The amount of water added for the hydrolysis is, preferably, equal to or more than 6.5 mL per gram of 4-aminobutyric acid.
Preferably, prior to isolating the sodium salt by filtration, a treatment step with activated carbon is included, at a temperature below the boiling point of water, so as to remove remains of sulfur compounds. Alternatively, this treatment may be carried out at room temperature, on completion of the hydrolysis step.
If desired, once the sodium salt has been obtained, the 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid may be obtained by neutralization of a solution of the salt with an acid stronger than the 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid itself, for example, hydrochloric acid, sulfuric acid, etc., in a way clearly within the reach of a man of the art.
Another way of obtaining the 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid consists of omitting the neutralization step on completion of the hydrolysis and precipitating the acid directly.
The process according to the invention is simple and economic, since it only requires simple industrial operations, the yields obtained are good and the necessary starting raw materials may be acquired on the marketplace.
The most important advantages of the process according to the invention consists of: 1) avoiding the use of PCl3, PCl5 or POCl3 as dehydrating agents in the phosphonation reaction, which obviates the handling of these reactants which are highly toxic and hazardous, as well as the release of HCI during the reaction; and 2) the fact that the presence of methanesulfonic anhydride keeps the reaction mixture fluid, without the occurrence of solidification, which makes stirring difficult.
The following examples are given for the purpose of providing the man of the art with a sufficiently clear and complete explanation of the present invention, but must not be considered as limitations on the essential aspects of the object thereof, as set forth in the foregoing paragraphs of this description.